| 1. |
- Chilunga, FP, et al.
(författare)
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Genome-wide DNA methylation analysis on C-reactive protein among Ghanaians suggests molecular links to the emerging risk of cardiovascular diseases
- 2021
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Ingår i: NPJ genomic medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 6:1, s. 46-
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Tidskriftsartikel (refereegranskat)abstract
- Molecular mechanisms at the intersection of inflammation and cardiovascular diseases (CVD) among Africans are still unknown. We performed an epigenome-wide association study to identify loci associated with serum C-reactive protein (marker of inflammation) among Ghanaians and further assessed whether differentially methylated positions (DMPs) were linked to CVD in previous reports, or to estimated CVD risk in the same population. We used the Illumina Infinium® HumanMethylation450 BeadChip to obtain DNAm profiles of blood samples in 589 Ghanaians from the RODAM study (without acute infections, not taking anti-inflammatory medications, CRP levels < 40 mg/L). We then used linear models to identify DMPs associated with CRP concentrations. Post-hoc, we evaluated associations of identified DMPs with elevated CVD risk estimated via ASCVD risk score. We also performed subset analyses at CRP levels ≤10 mg/L and replication analyses on candidate probes. Finally, we assessed for biological relevance of our findings in public databases. We subsequently identified 14 novel DMPs associated with CRP. In post-hoc evaluations, we found that DMPs in PC, BTG4 and PADI1 showed trends of associations with estimated CVD risk, we identified a separate DMP in MORC2 that was associated with CRP levels ≤10 mg/L, and we successfully replicated 65 (24%) of previously reported DMPs. All DMPs with gene annotations (13) were biologically linked to inflammation or CVD traits. We have identified epigenetic loci that may play a role in the intersection between inflammation and CVD among Ghanaians. Further studies among other Africans are needed to confirm our findings.
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| 2. |
- Chougule, Rohit A., et al.
(författare)
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Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation
- 2019
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Ingår i: npj Genomic Medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- The response of childhood acute lymphoblastic leukemia (ALL) to dexamethasone predicts the long-term remission outcome. To explore the mechanisms of dexamethasone resistance in B cell ALL (B-ALL), we generated dexamethasone-resistant clones by prolonged treatment with dexamethasone. Using RNA-sequencing and high-throughput screening, we found that dexamethasone-resistant cells are dependent on receptor tyrosine kinases. Further analysis with phosphokinase arrays showed that the type III receptor tyrosine kinase FLT3 is constitutively active in resistant cells. Targeted next-generation and Sanger sequencing identified an internal tandem duplication mutation and a point mutation (R845G) in FLT3 in dexamethasone-resistant cells, which were not present in the corresponding sensitive clones. Finally, we showed that resistant cells displayed sensitivity to second-generation FLT3 inhibitors both in vitro and in vivo. Collectively, our data suggest that long-term dexamethasone treatment selects cells with a distinct genetic background, in this case oncogenic FLT3, and therefore therapies targeting FLT3 might be useful for the treatment of relapsed B-ALL patients.
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| 3. |
- Gallego-Martinez, A, et al.
(författare)
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Using coding and non-coding rare variants to target candidate genes in patients with severe tinnitus
- 2022
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Ingår i: NPJ genomic medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 7:1, s. 70-
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Tidskriftsartikel (refereegranskat)abstract
- Tinnitus is the phantom percept of an internal non-verbal set of noises and tones. It is reported by 15% of the population and it is usually associated with hearing and/or brain disorders. The role of structural variants (SVs) in coding and non-coding regions has not been investigated in patients with severe tinnitus. In this study, we performed whole-genome sequencing in 97 unrelated Swedish individuals with chronic tinnitus (TIGER cohort). Rare single nucleotide variants (SNV), large structural variants (LSV), and copy number variations (CNV) were retrieved to perform a gene enrichment analysis in TIGER and in a subgroup of patients with severe tinnitus (SEVTIN, n = 34), according to the tinnitus handicap inventory (THI) scores. An independent exome sequencing dataset of 147 Swedish tinnitus patients was used as a replication cohort (JAGUAR cohort) and population-specific datasets from Sweden (SweGen) and Non-Finish Europeans (NFE) from gnomAD were used as control groups. SEVTIN patients showed a higher prevalence of hyperacusis, hearing loss, and anxiety when they were compared to individuals in the TIGER cohort. We found an enrichment of rare missense variants in 6 and 8 high-constraint genes in SEVTIN and TIGER cohorts, respectively. Of note, an enrichment of missense variants was found in the CACNA1E gene in both SEVTIN and TIGER. We replicated the burden of missense variants in 9 high-constrained genes in the JAGUAR cohort, including the gene NAV2, when data were compared with NFE. Moreover, LSVs in constrained regions overlapping CACNA1E, NAV2, and TMEM132D genes were observed in TIGER and SEVTIN.
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| 4. |
- Jacob, P., et al.
(författare)
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Clinical, genetic and structural delineation of RPL13-related spondyloepimetaphyseal dysplasia suggest extra-ribosomal functions of eL13
- 2023
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Ingår i: NPJ GENOMIC MEDICINE. - 2056-7944. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2-64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, retaining the same radiographic pattern of spondylar- and epi-metaphyseal dysplasia, but with varying severity of the hip and knee deformities. Two new missense variants, c.548 G>A, p.(Arg183His) and c.569 G>T, p.(Arg190Leu), and a previously known splice variant c.477+1G>A were identified, confirming mutational clustering in a highly specific RNA binding motif. Structural analysis and interpretation of the variants' impact on the protein suggests that disruption of extra-ribosomal functions of the protein through binding of mRNA may play a role in the skeletal phenotype of SEMD-RPL13. In addition, we present gonadal and somatic mosaicism for the condition.
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| 5. |
- Kerick, M., et al.
(författare)
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Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis
- 2022
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Ingår i: npj Genomic Medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals. © 2022, The Author(s).
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| 6. |
- Keskitalo, S, et al.
(författare)
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Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease
- 2019
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Ingår i: NPJ genomic medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 4, s. 14-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Mutations in several proteins functioning as endolysosomal components cause monogenic autoimmune diseases, of which pathogenesis is linked to increased endoplasmic reticulum stress, inefficient autophagy, and defective recycling of immune receptors. We report here a heterozygous TOM1 p.G307D missense mutation, detected by whole-exome sequencing, in two related patients presenting with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. The index patient suffered from recurrent respiratory tract infections and oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia, as well as an antibody deficiency. Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris. Consistent with previous knowledge on TOM1 protein function, we detected impaired autophagy and enhanced susceptibility to apoptosis in patient-derived cells. In addition, we noted diminished STAT and ERK1/2 signaling in patient fibroblasts, as well as poor IFN-γ and IL-17 secretion in T cells. The mutant TOM1 failed to interact with TOLLIP, a protein required for IL-1 recycling, PAMP signaling and autophagosome maturation, further strengthening the link between the candidate mutation and patient pathophysiology. In sum, we report here an identification of a novel gene, TOM1, associating with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. Other patient cases from unrelated families are needed to firmly establish a causal relationship between the genotype and the phenotype.
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| 7. |
- Lauschke, VM, et al.
(författare)
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Emerging strategies to bridge the gap between pharmacogenomic research and its clinical implementation
- 2020
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Ingår i: NPJ genomic medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 5:1, s. 9-
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Tidskriftsartikel (refereegranskat)abstract
- The genomic inter-individual heterogeneity remains a significant challenge for both clinical decision-making and the design of clinical trials. Although next-generation sequencing (NGS) is increasingly implemented in drug development and clinical trials, translation of the obtained genomic information into actionable clinical advice lags behind. Major reasons are the paucity of sufficiently powered trials that can quantify the added value of pharmacogenetic testing, and the considerable pharmacogenetic complexity with millions of rare variants with unclear functional consequences. The resulting uncertainty is reflected in inconsistencies of pharmacogenomic drug labels in Europe and the United States. In this review, we discuss how the knowledge gap for bridging pharmacogenomics into the clinics can be reduced. First, emerging methods that allow the high-throughput experimental characterization of pharmacogenomic variants combined with novel computational tools hold promise to improve the accuracy of drug response predictions. Second, tapping of large biobanks of therapeutic drug monitoring data allows to conduct high-powered retrospective studies that can validate the clinical importance of genetic variants, which are currently incompletely characterized. Combined, we are confident that these methods will improve the accuracy of drug response predictions and will narrow the gap between variant identification and its utilization for clinical decision-support.
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| 8. |
- Leblond, Claire S, et al.
(författare)
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Both rare and common genetic variants contribute to autism in the Faroe Islands.
- 2019
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Ingår i: NPJ genomic medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- The number of genes associated with autism is increasing, but few studies have been performed on epidemiological cohorts and in isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 individuals with autism, 136 of their relatives and 185 non-autism controls. Data from SNP array and whole exome sequencing revealed that individuals with autism had a higher burden of rare exonic copy-number variants altering autism associated genes (deletions (p=0.0352) or duplications (p=0.0352)), higher inbreeding status (p=0.023) and a higher load of rare homozygous deleterious variants (p=0.011) compared to controls. Our analysis supports the role of several genes/loci associated with autism (e.g., NRXN1, ADNP, 22q11 deletion) and identified new truncating (e.g., GRIK2, ROBO1, NINL, and IMMP2L) or recessive deleterious variants (e.g., KIRREL3 and CNTNAP2) affecting autism-associated genes. It also revealed three genes involved in synaptic plasticity, RIMS4, KALRN, and PLA2G4A, carrying de novo deleterious variants in individuals with autism without intellectual disability. In summary, our analysis provides a better understanding of the genetic architecture of autism in isolated populations by highlighting the role of both common and rare gene variants and pointing at new autism-risk genes. It also indicates that more knowledge about how multiple genetic hits affect neuronal function will be necessary to fully understand the genetic architecture of autism.
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| 9. |
- Li, Danyang, et al.
(författare)
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The influence of common polygenic risk and gene sets on social skills group training response in autism spectrum disorder
- 2020
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Ingår i: NPJ Genomic Medicine. - : Nature Publishing Group. - 2056-7944. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Social skills group training (SSGT) is a frequently used behavioral intervention in autism spectrum disorder (ASD), but the effects are moderate and heterogeneous. Here, we analyzed the effect of polygenic risk score (PRS) and common variants in gene sets on the intervention outcome. Participants from the largest randomized clinical trial of SSGT in ASD to date were selected (N = 188, 99 from SSGT, 89 from standard care) to calculate association between the outcomes in the SSGT trial and PRSs for ASD, attention-deficit hyperactivity disorder (ADHD), and educational attainment. In addition, specific gene sets were selected to evaluate their role on intervention outcomes. Among all participants in the trial, higher PRS for ADHD was associated with significant improvement in the outcome measure, the parental-rated Social Responsiveness Scale. The significant association was due to better outcomes in the standard care group for individuals with higher PRS for ADHD (post-intervention: β = −4.747, P = 0.0129; follow-up: β = −5.309, P = 0.0083). However, when contrasting the SSGT and standard care group, an inferior outcome in the SSGT group was associated with higher ADHD PRS at follow-up (β = 6.67, P = 0.016). Five gene sets within the synaptic category showed a nominal association with reduced response to interventions. We provide preliminary evidence that genetic liability calculated from common variants could influence the intervention outcomes. In the future, larger cohorts should be used to investigate how genetic contribution affects individual response to ASD interventions.
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| 10. |
- Olafsson, S, et al.
(författare)
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Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations
- 2017
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Ingår i: NPJ genomic medicine. - : Springer Science and Business Media LLC. - 2056-7944. ; 2, s. 24-
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Tidskriftsartikel (refereegranskat)abstract
- A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10−7, 4.3 × 10−9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
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